Method and compositions for maintaining glomerular filtration rate while inhibiting extracellular matrix accumulation

ABSTRACT

This invention provides a method of and compositions for increasing or maintaining glomerular filtration rate while preserving renal structure in a patient comprising administering an angiotensin II type 1 vascular receptor antagonist to the patient, independent of its effects on systemic blood pressure. The invention provides that, by administering an AII type 1 receptor antagonist, blood flow to the kidney can be improved without sacrificing intraglomerular pressure and therefore glomerular filtration and that even with this enhanced glomerular pressure and filtration, renal structure is preserved. Also provided is a method of screening AII type 1 receptor antagonists for the ability to maintain or increase glomerular filtration rate while decreasing mesangial matrix accumulation comprising the steps of administering the antagonist in an animal model characterized by decreased glomerular filtration rate and increased mesangial matrix accumulation and selecting the compounds that increase glomerular filtration rate while decreasing mesangial matrix accumulation.

This invention was made with government support under Grants DK-42159,DK-39547, DK-44757 and DK-37869 from the National Institutes of Health.The U.S. Government may have certain rights in this invention.

This application is a continuation of application Ser. No. 08/279,901,filed Jul. 25, 1994, now U.S. Pat. No. 5,512,580, which is afile-wrapper-continuation of Ser. No. 07/942,756, filed Sep. 9, 1992which status is abandoned.

Throughout this application various publications are referenced bynumbers within parentheses. Full citations for these publications may befound at the end of the specification immediately preceding the claims.The disclosures of these publications in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the state of the art to which this invention pertains.

BACKGROUND OF THE INVENTION

Angiotensin II (AII) is now known to act on the systemic vasculature andat several sites within the renal microcirculation with effects onvascular tone and vascular growth and extracellular matrix accumulation(1-6, 40). Angiotensin I converting enzyme inhibitor (ACEI) has beenused as a primary tool to control hypertension, increase organ bloodflow and preserve organ structure. However, while ACEI causesvasodilation, including within the renal circulation, its specificeffects, to decrease resistance of both glomerular afferent and efferentarterioles, can reduce glomerular capillary pressure and thereforefiltration. The renin angiotensin system (RAS) has been postulated to belinked to other vasoactive substances, notably bradykinin, which mayaccount for part of ACEI-induced vasodilatation (7-12). Assessment ofthe specific effects of endogenous AII on the renal circulation has beenlimited by this uncertain non-specific action of ACEI, and also by thepartial agonist effects of previously available AII analogues. Recently,the availability of both a specific nonpeptide AII type 1 receptorantagonist (AIIRA) which lacks agonist effects (13, 14), and a specificbradykinin receptor antagonist (15) has circumvented these difficulties.These developments are important, since it is frequently necessary toinhibit RAS effects in patients, including vasoconstriction, vasculargrowth and extracellular matrix accumulation.

Thus, there is a great need for a method of inhibiting RAS whilemaintaining or increasing GFR levels and protecting the kidney fromstructural injury. The invention provides that this can be accomplishedby antagonizing AII type 1 vascular receptor in a patient. Further, thisinvention provides that these beneficial effects on the kidney can beaccomplished independently of AII type 1 vascular receptor antagonisteffects on systemic blood pressure or other cardiac pathologies.

SUMMARY OF THE INVENTION

This invention provides a method of and compositions for increasing ormaintaining glomerular filtration rate while preserving renal structurein a patient comprising administering an angiotensin II type 1 vascularreceptor antagonist to the patient, independent of its effects onsystemic blood pressure. The invention provides that, by administeringthe AII type 1 receptor antagonist, blood flow to the kidney can beimproved without sacrificing intraglomerular pressure and thereforeglomerular filtration and that even with this enhanced glomerularpressure and filtration, renal structure is preserved. Also provided isa method of screening AII type 1 receptor antagonists for the ability tomaintain or increase glomerular filtration rate while decreasingmesangial matrix accumulation comprising the steps of administering theantagonist in an animal model characterized by decreased glomerularfiltration rate and increased mesangial matrix accumulation andselecting the compounds that increase glomerular filtration rate whiledecreasing mesangial matrix accumulation.

DESCRIPTION OF THE FIGURES

FIG. 1A-B shows individual glomerular capillary pressure (P_(GC)) valuesin acute water deprived (AWD) rats during baseline and followingangiotensin II receptor antagonist (AIIRA) or angiotensin I convertingenzyme (ACEI), showing markedly greater fall in P_(GC) with ACEI.

FIG. 2 shows mean arterial pressure (MAP) and glomerular filtration rate(GFR) in AWD rats treated with Furosemide. MAP decreased similarly inboth ACEI (Δ) and AIIRA (▴) treated groups. By contrast, GFR wasunchanged with ACEI (◯) and increased significantly with AIIRA ().

FIG. 3A-E is a summary of effects of ACEI and bradykinin antagonist(Hoe) in AWD+Furosemide rats. The decrease in glomerular capillarypressure (P_(GC)) with ACEI was restored with Hoe, primarily reflectingelevation in efferent arteriolar resistance, R_(E).

DETAILED DESCRIPTION OF THE INVENTION

This invention provides a method of maintaining or increasing glomerularfiltration rate (GFR) while inhibiting mesangial matrix accumulation ina patient. The method comprises administering an amount of an AII type 1vascular receptor antagonist that would maintain or increase GFR whilepreserving renal structure in the patient. The invention provides that,by administering the AII type 1 receptor antagonist, blood flow to thekidney can be improved without sacrificing intraglomerular pressure andtherefore glomerular filtration, and that even with this enhancedglomerular pressure and filtration, renal structure is preserved. Oneantagonist which has proven appropriate is L-158,809(5,7-dimethyl-2-ethyl-3- 2'-(1H-tetrazol-5yl)1,1'!-biphenyl-4-yl!-methyl!-3H-imidazo 4,5-b!pyridine). Otherappropriate antagonists include DuP 753 and any non-peptide AII type 1receptor antagonist now known or later discovered. Such antagonists canbe screened and selected by the methods provided herein.

The amount of an AII type 1 vascular receptor antagonist that canmaintain or increase GFR and inhibit mesangial matrix accumulation maynot be related to pressor dose. As used herein, the "pressor dosage"means the dosage of antagonist one would administer to normalizehypertension. In patients with an accumulation of mesangial matrix or ahistory of renal failure, the preferred dosage can be greater than thepressor dosage. Any pharmaceutically acceptable water or lipid solublecarrier would be appropriate as a carrier for antagonist compositions indoses greater than the pressor dosage.

AII type 1 receptor antagonist is administered to patients in whomsystemic/renal vasodilation is desired without compromising glomerularfiltration. Such patients would include those suffering fromhypertension with or without renal structural injury in whom maintenanceor increase in GFR can be accomplished with control of systemichypertension and inhibition of progressive renal structural injury. Suchpatients would also include those with ischemic cardiac disease, cardiacdysfunction following infarction, and cardiomyopathy, whether or notthese patients have systemic hypertension. Therefore, the inventionallows for the intentional simultaneous treatment of systemichypertension and function and structure of the kidneys utilizing an AIItype 1 receptor antagonist. As used herein, "hypertensive" means a bloodpressure above 150/90 mm Hg in adults which is above the normal range of120/80 mm Hg. The range for hypertension in children varies and isdependent on age and body size.

The invention also provides a method of screening AII type 1 receptorantagonists for the ability to maintain or increase GFR while decreasingmesangial matrix accumulation. The method comprises the steps ofadministering the antagonist in an animal model characterized bydecreased GFR and increased mesangial matrix accumulation and selectingthe compounds that maintain or increase GFR while decreasing mesangialmatrix accumulation. One such model to evaluate effects on glomerularfiltration, the AWD rat model, is set forth in the Examples. A model toexamine effects on glomerular filtration and structure chronically, therenal ablation model, is described in Reference 40.

RAS is important in regulating vasomotor tone in the systemic and organvasculatures. Interruption of the RAS to decrease vasoconstriction isoften a therapeutic goal, but is associated with variable effects on GFR(6, 17, 21-30). Studies in the AWD rat, a model characterized byhypoperfusion and hypofiltration with activation of the RAS, examinedthese issues. Antagonizing AII actions by inhibition of convertingenzyme vasodilated the systemic and renal circulations; systemic bloodpressure decreased and renal plasma flow increased, however, there wasno improvement in GFR. Analysis of the microcirculatory hemodynamicsrevealed that arteriolar resistances decreased, particularly in theefferent arteriole, which contributed to the increase in glomerularplasma plow rate, Q_(A). However, the efferent arteriolar dilatationalso caused a profound fall in P_(GC) (by 16 mm Hg), which offset theeffects of increases in glomerular plasma flow rate, Q_(A) and ultrafiltration and resulted in no improvement in single nephron glomerularfiltration rate (SNGFR). These findings are in accord with reports thatinhibition of RAS can increase, decrease, or leave unchanged the rate offiltration, and emphasize that the net effect on GFR depends upon thebalance of AII's effects on afferent arteriolar resistance, R_(A), R_(E)and K_(f) (6, 16, 17, 24). In more severe hemodynamic decompensation,glomerular filtration may be critically dependent on heightened RASwhich promotes efferent arteriolar maintenance of P_(GC) and GFR.Removal of this critical compensation then leads to a fall in GFR (17).This notion is supported by the observation that decreased GFR andazotemia develop in patients on ACEI with superimposed circulatorystress such as blood loss, addition of diuretics or other fluid loss,which overwhelms already maximal compensation by RAS (22, 23, 25-28,31). It should be emphasized that hypofiltration occurs even in theabsence of profound systemic hypotension (22, 31). Further, for similardecrease in systemic blood pressure, hypofiltration occurs morefrequently when RAS is inhibited compared with systemic vasodilatationachieved with maneuvers not involving RAS inhibition. These findingsthen implicate renal, rather than systemic, changes which areresponsible for decreasing filtration.

The effects of a specific AII type I receptor antagonist (AIIRA) wereexamined, as set forth in the following Examples. The angiotensin type Ireceptor is one of two angiotensin receptor types identified in humans,and is the subtype that mediates cardiovascular actions of AII (32). Therenal distribution of the mRNA of this receptor was examined in ourrecent in situ hybridization studies. No signal was detected ininterlobular arteries while this signal was prominent in vesselsregulating blood flow and filtration, including both afferent andefferent arterioles and the mesangium (33). In contrast to ACEI, thepresent data shows that antagonizing type I AII vascular receptor causedrenal vasodilatation, which was accompanied by a striking increase infiltration (Table 1, FIG. 2). This difference was apparent betweenperiods within an animal and also between groups. While the magnitude ofdecrease in systemic blood pressure and increase in Q_(A) were similar,antagonism of AII with a receptor antagonist resulted in lesserreduction in efferent arteriolar tone than inhibition of ACE. This isreflected by the changes in P_(GC). Thus, although systemic bloodpressures was decreased to the same degree by both ACEI and AIIRA, ACEIcaused P_(GC) to fall by 16 mm Hg, compared with 7 mm Hg fall followingAIIRA.

Differences in the microcirculatory hemodynamic changes afterinterrupting the RAS at these different sites of action, i.e. at theinteraction of ligand and type I receptor vs. inhibition of conversionof angiotensin I to AII, demonstrate that other AII effects or non-AIIactions contribute, at least in part, to the dyssynchrony between renalvasodilatation and filtration following ACEI. In this regard,circulating levels of AII modulate expression of the genes of the RAS,including renin, angiotensinogen and ACE (34). Since circulating AIIlevels are higher after AIIRA than ACEI treatment (35), this higherlevel of unbound AII can interact with other vasoactive substances, orbind with type II receptor or other angiotensin binding proteins. Thepossibility of additional, non-AII effects (e.g. interaction withvasodilators) is of interest in view of the previous observation thatrats with renal hypoperfusion because of congestive heart failure andAWD developed a paradoxical fall in efferent arteriolar tone in responseto superimposed reduction in renal perfusion pressure (17). In thissetting, the expected renal vasodilatation is postulated to reflectattenuation of AII actions. However, the observations demonstrate thatthe failure to increase or actually even decreasing GFR during suchrenal vasodilatation is not simply attenuation of AII effects, rather itis an active vasodilatation.

Some vasodilators are associated with RAS, including bradykinin,endothelium-derived relaxing factor and prostaglandins, although thedata demonstrates that the latter does not have a major role in thisregard. Of note, angiotensin I converting enzyme inhibitors inactivatekininase II, a kinin-degrading enzyme which would result in accumulationof bradykinin. Bradykinin's contribution to ACEI-induced vasodilatationhas been controversial (8-12, 36-38). There is accumulating evidencethat kinins play an important role in regulating renal function,including recent evidence that kinins can be formed in the renalcirculation. This is of particular relevance since among isolated rabbitinterlobular, efferent and afferent arteriolar preparations, bradykinincaused marked vasodilatation only in the efferent arteriole (39).Bradykinin's role in the ACEI-induced vasodilatation was investigated,in particular whether the dramatic decrease in efferent arteriolarresistance is related to the enhanced bradykinin activity. The data inanimals treated with ACEI clearly show that antagonizing bradykininopposed the decrease in efferent arteriolar resistance effected byconverting enzyme inhibition (FIG. 3D). This in turn caused an elevationin glomerular pressure which was pivotal in increasing GFR.

Interruption of the RAS by ACEI is now used in many circumstances tolower blood pressure, to effect afterload reduction, decreaseproteinuria and also to forestall chronic deterioration in renalfunction. While vasodilatation and renal sparing is a desirabletherapeutic end point in the kidney, a decrease in vascular resistancecan cause not only renal vasodilatation but also may decrease glomerularcapillary pressure, and therefore remove an important compensatorymechanism to maintain GFR. These data show that renal vasodilatationfollowing inhibition of angiotensin I converting enzyme is at least inpart related to bradykinin. These data further indicate that inconditions where high P_(GC) is crucial in maintaining GFR, activationof bradykinin by ACEI can precipitate severe compromise in GFR, and thatthis untoward effect can be largely avoided with a more specificvasodilator for antagonism of AII effects.

EXAMPLES

Experiments were done in adult male Munich-Wistar rats. All animals weredeprived of water for 48 hours (acute water deprivation, AWD), a modelcharacterized by hypoperfusion, hypofiltration and activated RAS (6, 16,17). Renal function was then assessed as described in detail below. AWDdecreased the body weight, on average, by 15%.

Group 1 AWD treated with ACEI (n=6). Rats were prepared formicropuncture as previously described (6, 16, 17). Briefly, underInactin anesthesia (70 mg/kg body wt i.p., BYK, Konstanz, Germany),tracheotomy was performed, and indwelling polyethylene catheters wereinserted into the femoral artery and vein and the jugular vein for bloodsampling, monitoring of systemic blood pressure, and infusion of inulinand plasma, as previously described (6, 16, 17). Determinations ofSNGFR, hydraulic pressures in glomerular capillaries (P_(GC)), proximaltubules (P_(T)), and efferent arterioles were made. Femoral arterial(C_(A)) and efferent arteriolar (C_(E)) plasma protein concentrationswere also obtained, permitting calculation of glomerular plasma flowrate (Q_(A)) and ultrafiltration coefficient (K_(f)), as well asresistances of afferent (R_(A)) and efferent (R_(E)) arterioles. Colloidosmotic pressures of plasma entering and leaving the glomerularcapillaries were estimated from C_(A) and C_(E) using derivations ofDeen et al. (18, 19). Details of the analytical procedure for inulin inplasma and nanoliter tubule fluid samples, and that for C_(A) and C_(E)are described elsewhere (18, 19). After baseline measurements andcollections, each rat was treated with ACEI (enalapril, 0.3 mg/kg i.v.bolus, then 0.3 mg/hr continuous i.v. infusion). After 60 minutes,micropuncture measurements were repeated.

Group II AWD treated with AIIRA and ACEI (n=6). Rats were prepared as inGroup I except that, after baseline measurements, AIIRA (4 mg/kg body wti.v. as bolus and then as continuous infusion, L-158,809, Merck, Sharp &Dohme), a specific type I angiotensin receptor II antagonist, wasstarted. Renal micropuncture measurements were performed 1 hour afterAIIRA was started. AIIRA was then discontinued and ACEI was infused asin Group I with repeat micropuncture measurements after 1 hour. Sincethe AIIRA has half life exceeding 6 hours in the rat (14) and effects inthe ACEI period may in part reflect alterations of the RAS afterreceptor inhibition, we studied separate groups of animals treated witheither ACEI or AIIRA.

Groups IIIA and B, AWD+Furosemide, treated with ACEI (n=6) or AIIRA(n=6). To confirm differences in renal function between ACEI versusAIIRA under conditions with extreme stimulation of the RAS, we studiedanimals that received furosemide in addition to water deprivation.Furosemide (2.5 mg/kg body wt i.p.) was administered at the start ofwater deprivation and again the next day which was at least 24 hoursprior to micropuncture/clearance studies to avoid confounding effects offurosemide activation of tubuloglomerular feedback. Following surgicalpreparation, baseline clearance studies were obtained as previouslydescribed (6, 16, 17). The animals were then treated with either ACEI(Group IIIA, n=6) or AIIRA (Group IIIB, n=6), as described above.Measurements were repeated 60 minutes later.

Group IVA and B, AWD+Furosemide, treated with ACEI+bradykinin receptorantagonist, Hoe (n=9), or Hoe (n=6). These animals were prepared asGroup IIIA (baseline, then ACEI) but, in addition, a third period ofstudy was added. Thus, during ACEI treatment renal hemodynamic studieswere performed, and then a newly developed bradykinin antagonist wasadded (0.1 mg/kg body wt i.v. bolus and s.c, Hoe-140, HOECHST,Frankfurt, Germany). Micropuncture measurements were then performed. Thebradykinin antagonist has previously been shown to be highly protectivein vivo, completely preventing bradykinin-induced systemic hypotensionafter 1 hour and with only minimal hypotension (˜5% decrease in bloodpressure) 2 hours following subcutaneous administration (15). Group IVBrats were treated identically, except that no ACEI was given. The samedose of Hoe-140 was administered before measurement of renal clearancesat 1 hour.

To assess a potential role for prostaglandins in the effects of ACEIversus AIIRA, a separate group was pretreated with indomethacin, 2 mg/kgbody wt/hr i.v. Following micropuncture/clearance studies, the animalsreceived either ACEI (n=4) or AIIRA (n=4) as above, and renal studieswere repeated.

Group 1, AWD treated with ACEI. Whole kidney GFR, SNGFR, and Q_(A)(0.46±0.07 ml/min, 16.2±1.9 nl/min, and 53±6 nl/min, respectively) werecharacteristic of the hypoperfusion/hypofiltration pattern of renalhemodynamics and distinct from normal euvolemic rats (6, 16, 17). Theseparameters reflect higher than normal afferent and efferent arteriolarresistances (0.402±0.044 mmHg.min/nl and 0.543±0.085, respectively).Inhibition of angiotensin I converting enzyme activity decreased MAPfrom 107±6 mmHg to 94±5, and caused renal dilatation. Thus, Q_(A) valuesincreased to 102±24 nl/min, due to a decrease in arteriolar resistances,particularly of the efferent arteriole (from 0.543±0.085 mmHg.min/nl to0.235±0.048, p<0.025). The fall in R_(E) was apparent in the profounddecrease in the intraglomerular pressure; P_(GC) fell from the higherthan typical euvolemic value of 65±2 mmHg to 49±1 (p<0.005). Asexpected, inhibition of AII activity caused an increase in the value ofK_(f) 1.020±0.240 nl/(min.mmHg) vs. 2.700±0.600, p<0.025!. Thecumulative effect of these changes was the lack of consistentimprovement in filtration (GFR 0.46±0.07 vs. 0.54±0.06 ml/min, p NS). Inthe next set of experiments, the mechanism of AII's actions on theglomerular microcirculation was explored by interrupting the RAS atdifferent sites in the same animals.

Group II AWD treated with AIIRA and ACEI Group II rats were preparedidentically to Group I and again showed the typical renal hypoperfusionof AWD. In contrast to Group I ACEI-treated rats, both GFR (p<0.05) andSNGFR (p<0.025) increased significantly with AIIRA. Evaluation ofindividual parameters that affect filtration revealed vasodilatation,particularly due to a fall in efferent arteriolar resistance (p<0.05).Of note, while P_(GC) fell from 67±3 mmHg to 60±2 (p<0.05), thisdecrease was markedly less than that observed in Group I ACEI-treatedrats, where average Pac decreased by 16 mmHg. Whether inhibition ofconverting enzyme in the setting of previous antagonism of AII receptorhad an additional independent effect on filtration was then examined.

ACEI following AIIRA caused a profound fall in the rate of filtration:GFR and SNGFR fell even below baseline (Table 1). Of note, the profoundhypofiltration occurred in the face of renal dilatation. Q_(A) increasedfurther to 134±19 nl/min (p<0.025 vs. baseline), largely reflecting amarked decrease in the efferent arteriolar resistance. As in Group 1,this was associated with a precipitous decrease in P_(GC), which was onaverage 15 mmHg lower than baseline value.

Groups IIIA and B, AWD+Furosemide, treated with ACEI or AIIRA. Due tothe potential persisting actions of the long lasting AIIRA, separategroups of animals were treated with ACEI (Group IIIA) or AIIRA (GroupIIIB). To confirm differences in renal microcirculatory responses toACEI versus AIIRA under conditions with extreme stimulation of the RAS,these animals received furosemide in addition to AWD. Group III ratswere more profoundly dehydrated than Groups I and II as evidenced byhigher hematocrit (60±1% vs. 52±1 and 51±1, respectively, for Group IIIversus Group I and 2, p<0.0005). MAP decreased from baseline in bothGroups IIIA and IIIB with treatment: 93±6 mm Hg to 87±5 (p<0.025), and93±6 mm Hg to 83±3 (p<0.05), respectively. Similar to Groups I and II,ACEI did not affect GFR (0.61±0.04 ml/min versus 0.61±0.05). In contrastto ACEI, inhibition of AII with receptor antagonist resulted in markedimprovement in GFR which, on average, increased from 0.51±0.07 ml/min to0.72±0.09 (p<0.01).

Group IVA and B, AWD+Furosemide, treated with ACEI and bradykininreceptor antagonist, Hoe (n=9) or Hoe alone (n=6). To further explorethe mechanisms underlying these differing effects on the rate ofglomerular filtration, we studied the potential contribution ofbradykinin, as ACEI, unlike AIIRA, acts as a kininase inhibitor. Forthis purpose, we evaluated the renal microcirculation in response to aspecific bradykinin receptor antagonist. ACEI decreased MAP (98±3 mm Hgto 90±2) and increased renal perfusion without improving hypofiltration,GFR 0.50±0.08 ml/min versus 0.58±0.08, SNGFR 21±2 nl/min versus 22±2.The individual parameters are shown in FIG. 3, again emphasizing themarked decrease in P_(GC) following ACEI (63±4 mm Hg vs. 53±3, p<0.005).The contribution of bradykinin was evaluated in the third period. MAPwas unchanged from that during ACEI treatment. Filtration increasedsignificantly; GFR rose to 0.71±0.10 ml/min (p<0.005 vs. ACEI), andSNGFR increased to 28±3 nl/min (p<0.05 vs. ACEI). This improvement infiltration was due to an increase in glomerular pressure which returnedtoward the baseline level (62±6 mmHg, p<0.05 ACEI vs. Hoe), reflectingreturn of efferent arteriolar resistance to baseline levels, 0.312±0.050mmHg.min/nl. The value for K_(f) was not affected by the bradykininantagonist 1.735±0.320 nl/(min.mmHg) vs. 1.465±0.472, ACEI vs. Hoe,respectively!. In Group IVB, AWD+furosemide animals treated with thebradykinin antagonist alone, GFR was 0.81±0.10 ml/min at baseline, withno significant change after bradykinin antagonist, 0.89±0.19 ml/min.

Separate rats were treated with either ACEI or AIIRA after prostaglandininhibition with indomethacin. SNGFR showed ˜20% increase over baselineafter ACEI versus 100% increase after AIIRA (p<0.05), Q_(A) increased˜70% versus ˜140%, and R_(A) decreased ˜30% versus ˜60% (p<0.05),respectively. These findings are taken to suggest that prostaglandinsare not the major intermediary mechanism for the greater divergencebetween vasodilatation and filtration seen after ACEI versus AIIRA.

The likelihood of achieving success in humans based on these specificfindings in the rat is based on several facts. First, systemic and renalhemodynamics in normal and disease states have been investigatedextensively in the rat and found to be relevant to clinical conditionsin humans. Second, the RAS is phylogenetically tightly preserved, withactivation in response to similar stimuli in both rats and humans, andthe type 1 vascular receptor is found in both rats and humans with over90% homology. Further, inhibition of the RAS by ACEI has been shown tohave parallel effects in both rats and humans. Therefore, inhibition ofRAS by the AII type 1 vascular receptor antagonist is expected to havethe same effects in humans as shown in these rat studies.

The preceding examples are intended to illustrate but not limit theinvention. While they are typical of those that might be used, otherprocedures known to those skilled in the art may be alternativelyemployed.

                                      TABLE 1                                     __________________________________________________________________________    Systemic and Renal Microcirculatory Parameters in AWD Rats in Response        to                                                                            Inhibition of the Renin Angiotensin System                                    MAP      GFR   SNGFR Q.sub.A                                                                             P.sub.GC                                                                           R.sub.A                                                                              R.sub.E K.sub.f                        mmHg     ml/min                                                                              nl/min                                                                              nl/min                                                                              mmHg mmHg.min/ml                                                                          mmHg.min/nl                                                                           nl/(min.mmHg)                  __________________________________________________________________________    Baseline                                                                           95 ± 2                                                                         0.46 ± 0.07                                                                      25.2 ± 2.5                                                                       82 ± 7                                                                           67 ± 3                                                                          0.170 ± 0.015                                                                     0.333 ± 0.042                                                                      1.322 ± 0.368               AIIRA                                                                              88 ± 2*                                                                        0.59 ± 0.05*                                                                     30.2 ± 2.3*                                                                      111 ± 21                                                                         60 ± 2*                                                                         0.143 ± 0.023                                                                     0.240 ± 0.037*                                                                     1.968 ± 0.311               ACEI 89 ± 2*                                                                        0.41 ± 0.04‡                                                          21.5 ± 1.1‡                                                            134 ± 19*                                                                        52 ± 1*‡                                                            0.169 ± 0.016                                                                     0.159 ± 0.032*                                                                     2.188 ± 0.381               __________________________________________________________________________     AWD, acute water deprivation;                                                 MAP, mean arterial pressure;                                                  GFR, whole kidney glomerular filtration rate;                                 SNGFR, single nephron GFR;                                                    Q.sub.A, initial glomerular plasma flow rate;                                 P.sub.GC, glomerular capillary hydraulic pressure;                            R.sub.A, afferent arteriolar resistance;                                      R.sub.E, efferent arteriolar resistance;                                      K.sub.f, glomerular capillary ultrafiltration coefficient.                    *P > 0.05 vs. baseline;                                                       ‡P > 0.05 vs. AIIRA (specific P values in the text).          

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What is claimed is:
 1. A method of maintaining or increasing glomerularfiltration rate while inhibiting mesangial matrix accumulation in apatient comprising administering a matrix accumulation inhibiting amountof a suitable angiotensin II type 1 vascular receptor antagonist to thepatient.
 2. The method of claim 1, wherein the systemic blood pressureis lowered during the process of inhibiting mesangial matrixaccumulation while maintaining or increasing glomerular filtration rate.3. The method of claim 1, wherein the mesangial matrix accumulationinhibiting amount of angiotensin II type 1 vascular receptor antagonistadministered is greater than the pressor dosage.
 4. The method of claim1, wherein the glomerular filtration rate relative to systemic bloodpressure is increased from the hypertensive range after administrationof angiotensin II type 1 vascular receptor antagonist.
 5. The method ofclaim 1, wherein the glomerular filtration rate relative to systemicblood pressure is increased from the normal range after administrationof the angiotensin II type 1 vascular receptor antagonist.